The offspring of consanguineous relations have an average increased risk of 2-4% of congenital/genetic disorders and early mortality. However, on an individual level the exact risk figure can vary to a great extent.
The children of consanguineous couples represent a considerable group, since an estimated 10.5% of all children worldwide have consanguineous parents . This frequency is, however, very unevenly distributed between countries. In some countries the current percentage of consanguineous marriages is higher, and may even exceed 50%, while in many others the percentage does not surpass 1% [2, 3]. Worldwide, every year over 130 million infants are born , which leads to the conclusion that the considerable number of 13.5 million of those children have consanguineous parents.
Autosomal recessive (AR) inheritance
A child affected by an AR disease has inherited a pathological allele from both parents who are carriers of such an allele. If both parents are carriers, all of their children have a 25% chance of being affected.
Risk is proportional to degree of relatedness of the parents
The risk of being a carrier couple is on the one hand proportional to the frequency of a pathological allele in the population, and on the other hand proportional to the coefficient of inbreeding (F), which is defined as the probability that a child inherits two identical copies of an allele from one or more common ancestors. The closer the partners of a consanguineous couple are related, the greater the chance that they will have genetic information identical-by-descent (IBD). When the amount of DNA-sharing increases, this also increases the chance of sharing a particular pathological allele IBD and therefore the chance of having affected offspring with an AR disease. Theoretically, the likelihood that an allele passed on to the next generation will be an identical copy of the allele of a common ancestor passed on by the other partner is 1/16 (F = 1/16) for first cousins' offspring, whereas for second cousins' offspring, this is 1/64. For unions less closely related than second cousins, the risk of having an affected child is only marginally increased.
Studies among first-cousin couples, the most prevalent type of consanguineous marriage, show that the excess risk for their offspring of having a significant birth defect ranges from 1.7-2.8% . The risk for mortality in early life (i.e. from six months of gestation to an average of ten years of age) in the offspring of first-cousin marriages is estimated at 3.5% . For this latter figure it remains difficult to control for the effects of non-genetic variables. Causes of mortality that are related to other (sociodemographic) variables, like maternal illiteracy, maternal age and birth interval, may, in themselves, lead to a higher rate of neonatal and early childhood mortality and could be confounders [1, 6]. Considering that over 10% of all children worldwide have consanguineous parents, combined with the excess risk of 2-4% per first-cousin couple, the conclusion can be drawn that the global burden of pre-reproductive mortality and morbidity for the children and their families is substantial. The proportion of first-cousin marriages among consanguineous couples is estimated to be at least 70% [A.H. Bittles, personal communication]. From this number we can infer that the extra number of affected children born to first-cousin parents is approximately 190,000 to 380,000 each year. The total number of cases due to consanguinity, however, must be higher, since our estimate does not include the affected children born to consanguineous parents who are related in another way.
Only the minority of consanguineous couples have an increased risk
If one compares the 2-4% additional risk of congenital/genetic disorders and/or early death in children of a first-cousin couple, to the 25% risk of a couple in which both man and wife are carriers of an AR disorder, one has to conclude that a maximum of 8-16% of all first-cousin couples are at high risk (25%; or higher in case of carriership of more than one disorder), while at least 84-92% of all first-cousin couples have a normal risk, comparable to unrelated parents.
Risk assessment in practice
When a consanguineous couple is referred for risk assessment, e.g. to a clinical genetics centre, best practice prescribes that a thorough family history will be taken . For an average non-consanguineous couple, a risk of 2-3% of having a child with a genetic/congenital disorder is present. For a first-cousin couple, an additional risk of 2-4% should be added to this basic risk. The risk can further increase if a family history for a genetic disorder exists. A more precise risk estimate for that particular disease can then be assessed by risk calculation or - if possible and desired - by carrier testing. If the population of origin of the couple is known to have a high risk of a specific recessive disorder, carrier screening could be offered as well.
A typical characteristic for AR disorders is the fact that frequently there are no previous affected members within the family, since affected family members most often can be found in only one sibship. When there is no history of diseases in the family of a consanguineous couple that comes for preconception counselling, there is still an additional average risk close to 2-4%. However, it is currently not possible to determine who is at 25% (or more) risk, and who has no increased risk. Given this uncertainty, being able to give a more precise risk figure could have important consequences for counselling.
The actual amount of DNA IBD in children of first cousins can be different from the theoretical 1/16 due to a stochastic variation which is caused by the random recombinations in common ancestral loops. This causes a significant variability between couples with the same F-value . A simulation study performed by Leutenegger et al. also showed that considerable variability in estimates of the coefficient of inbreeding derived from whole genome analyses can be found. For example, at first-cousin level, individuals with an expected F = 0.0625 can have from 0.03-0.12 of their genome IBD . Clearly, this variability could significantly alter the probability that a recessive disease gene will be expressed.
Variation by hidden ancestral loops
A difference in DNA-sharing may also be present while comparing couples with a similar inbreeding coefficient when the estimated coefficient is based on limited available genealogical data. Distant consanguineous loops often remain unknown, which can lead to an underestimation of the inbreeding coefficient . Genealogy-based studies have indicated that after 3-4 generations of cumulative inbreeding and with multiple loops of consanguinity, as would occur in many highly inbred communities, the progeny of first-cousin unions may have F values up to 0.1484, which likewise would be expected to significantly influence recessive gene expression . The variability in DNA sharing in practice was also shown by Woods et al. who studied children with AR disorders whose parents were consanguineous . By using SNP analysis, they found that in individuals with a recessive disease whose parents were first cousins, on average 11% of their genomes were homozygous, as opposed to the 6.25% one would expect.
On the basis of the above-mentioned considerations and observations, we hypothesize that consanguineous parents of a child with an AR disorder will have more DNA IBD than similarly-related parents who have only had healthy children. This hypothesis leads to the objective of our present study, namely to establish whether the amount of DNA IBD in partners of consanguineous couples with a child affected by an AR disease is indeed increased compared to its proportion in partners of consanguineous couples who have healthy children only. If so, this result might be applied to improve risk assessment in consanguineous couples.